Exposure to pathogens leads to the sustained production of serum antibodies for a life-time. For instance, humans immunized with smallpox vaccine exhibit stable levels of neutralizing antibodies in their serum for over 75 years. Antibodies are produced by plasma cells and these cells are critical effectors of the humoral immune system both in health (responses to pathogens) and in disease (autoimmunity) and hence, it is important to better understand how these cells are regulated and maintained. CD28 is a cell surface protein that is critical for the activation of nave T cells. Interestingly, CD28is expressed also on plasma cells and multiple myeloma cells. Here we provide evidence that CD28 is expressed on both short-lived as well as long-lived plasma cells in the bone marrow. Very little is known about the function of CD28 on plasma cells. We also demonstrate that short- and long-lived plasma cells also express the ligands for CD28, B7.1 and B7.2. Based upon our compelling preliminary data, our central hypothesis is that CD28/B7 molecules are critical for the regulation of plasma cell function and modulation of this interaction using soluble CD28 or B7 molecules will enhance immune responses in vivo. We will test our central hypothesis by pursuing three specific aims. We will determine the extent to which CD28 (Aim 1) and B7. /B7.2 (Aim 2) affects plasma cell function and longevity and determine whether soluble CD28 or B7 can be used to enhance host immune responses to poorly-immunogenic H5N1 avian influenza vaccine (Aim 3). The proposed work is significant, because upon completion, we will have a better understanding of how CD28 and or B7 molecules modulate function and longevity of plasma cells. This could potentially be used to (a) enhance vaccine-induced Ab responses or (b) down modulate self-reactive plasma cells in autoimmune disorders.